The invention relates to the synthesis of individual di- and tri-substituted-1,4-diazacyclic compounds having 6- to 8-atoms in the cyclic ring, their corresponding 1,6-diketo-2,5-diazacyclic compounds and similar 1,4-diazacyclic ring compounds having one ring carbonyl gorup and 6-8 atoms in the ring, and libraries of such compounds. The present invention further relates to methods of preparing and using the libraries of compounds as well as individual compounds of the libraries.
Heterocyclic compounds having a high degree of structural diversity have proven to be broadly and economically useful as therapeutic agents. [For reviews on solid phase organic synthesis, see: (a) Gallop, M. A. et al., J. Med. Chem., 1994, 37, 1233. (b) Gordon, E. M. et al., J. Med. Chem., 1994, 37, 1385. (c) Thompson, L. A. et al., Angew. Chem. Int. Ed. Engl., 1996, 35, 17.(e) Hermkens, P. H. H. et al., Tetrahedron, 1996, 52, 4527. (f) Nefzi, A. et al., Chem. Rev. 1997, 97, 449.] A number of approaches have been reported for the solid phase synthesis of diketopiperazine derivatives: Gordon and Steele developed a strategy for the solid phase synthesis of diketopiperazines based on reductive amination on the solid support [Gordon, D. et al., BioMed. Chem. Lett., 1995, 5, 47]. A similar approach has been published by Krchnàk and co-workers for the synthesis of persubstituted 2,5-diketopiperazines [Krchnàk, V. et al., In Molecular Diversity and Combinatorial Chemistry: Libraries and Drug Discovery; Chaiken, I. M., Janda, K. D. Eds., American Chemical Society: Washington, DC. 1996, pp 99-117], and Scott and co-workers developed an alternative strategy for the synthesis of a similar diketopiperazine library using bromocarboxylic acids and a range of amines [Scott, B. O. et al., Mol. Diversity, 1995, 1, 125].
The process of discovering new therapeutically active compounds for a given indication involves the screening of all compounds from available compound collections. From the compounds tested one or more structure(s) is selected as a promising lead. A large number of related analogs are then synthesized in order to develop a structure-activity relationship and select one or more optimal compounds. With traditional one-at-a-time synthesis and biological testing of analogs, this optimization process is long and labor intensive. Adding significant numbers of new structures to the compound collections used in the initial screening step of the discovery and optimization process cannot be accomplished with traditional one-at-a-time synthesis methods, except over a time frame of months or even years. Faster methods are needed that allow the preparation of up to thousands of related compounds in a matter of days or a few weeks. This need is particularly evident when it comes to synthesizing more complex compounds, such as the 4,5-disubstituted-2,3-diketopiperazine and 1,4,5-trisubstituted-2,3-diketopiperazine compounds of the present invention.
Solid-phase techniques for the synthesis of peptides have been extensively developed and combinatorial libraries of peptides have been generated with great success. During the past four years there has been substantial development of chemically synthesized combinatorial libraries (SCLs) made up of peptides. The preparation and use of synthetic peptide combinatorial libraries has been described for example by Dooley in U.S. Pat. No. 5,367,053; Huebner in U.S. Pat. No. 5,182,366; Appel et al in WO PCT 92/09300; Geysen in published European Patent Application 0 138 855 and Pimmg in U.S. Pat. No. 5,143,854. Such SCLs provide the efficient synthesis of an extraordinary number of various peptides in such libraries and the rapid screening of the library which identifies lead pharmaceutical peptides.
Peptides have been, and remain, attractive targets for drug discovery. Their high affinities and specificities toward biological receptors as well as the ease with which large peptide libraries can be combinatorially synthesized make them attractive drug targets. The screening of peptide libraries has led to the identification of many biologically-active lead compounds. However, the therapeutic application of peptides is limited by their poor stability and bioavailability in vivo. Therefore, there is a need to synthesize and screen compounds which can maintain high affinity and specificity toward biological receptors but which have improved pharmacological properties relative to peptides.
Combinatorial approaches have recently been extended to xe2x80x9corganicxe2x80x9d or non-peptide libraries. The organic libraries to the present, however, are of limited diversity and generally relate to peptidomimetic compounds; in other words, organic molecules that retain peptide chain pharmacophore groups similar to those present in the corresponding peptide. Although the present invention is principally derived from the synthesis of dipeptides, the dipeptides are substantially modified. In short, they are chemically modified through alkylation, acylation, reduction, and cyclization into the subject diketopiperazines, thus providing mixtures and individual compounds of substantial diversity.
Significantly, many biologically active compounds contain diketopiperazines. Diketopiperazines are conformationally constrained scaffolds that are quite common in nature, and many natural products containing a diketopiperazine structure have been isolated that encompass a wide range of biological activities. Included in such compounds are inhibitors of the mammalian cell cycle reported by Cui et al., J. Antibiot., 47:1202 (1996), inhibitors of plasminogen activator-1, and topoisomerase reported by Charlton et al., P. Thromb. Haeomast., 75:808 (1996) and Funabashi et al., J. Antibiot., 47:1202 (1994). Diketopiperazines have been reported by Terret et al., Tetrahedron, 51:8135 (1995) to be useful as ligands to the neurokinin-2 receptor. Barrow et al., Bioorg. Med. Chem. Lett., 5:377 (1996) found diketopiperazines to be competitive antagonists to Substance P at the neurokinin-1 receptor. Because, diketopiperazine moieties are found in many biologically active compounds and are known to have useful therapeutic implications, there is a need to further study and develop large numbers of 2,3-diketopiperazine compounds and their analogues of larger ring size.
This invention satisfies these needs and provides related advantages as well. The present invention overcomes the known limitations to classical organic synthesis of cyclic 2,3-diketopiperazines. Existing reported approaches for the synthesis of diketopiperazines describe only the synthesis of 2,5-diketopiperazines, the present invention provides a large array of diverse 1,4,5-trisubstituted- and 4,5-disubstituted-2,3-diketopiperazine compounds that can be screened for biological activity, related piperazine and larger ringed compounds, as described below, that exhibit biological activity.
The invention provides a rapid synthesis of (1-substituted or 1,2-disubstituted)-(4-aminoalkyl)-1,4-diazacyclic compounds having 6- to 8-atoms in the cyclic ring and the corresponding 1,6-diketo-(2-substituted or 2,3-disubstituted)-(5-aminoalkyl)-2,5-diazacyclic compounds and related cyclic amino amides and cyclic keto diamines of Formula I, hereinafter, and further provides combinatorial libraries that contain those compounds. The naming system used herein is understood to not be in conformance with naming systems usually used in organic chemistry, and relies upon the structural features common to all of the contemplated compounds as is discussed below.
It is first to be noted that the contemplated compounds can have one of two structure types that each contain a cyclic compound in which two nitrogen atoms are present in the ring at what can be considered positions 1 and 4. The first compound type contains one or two carbonyl groups that can be bonded to a ring amine, in which the first amine contains another amine at the 2- through 7-position of an alkyl group bonded to that first amine, and in which the second amine also can also contain a substituent group. The second compound type contains the same structural features as the first type, but lacks the one or two carbonyl groups and is a cyclic compound containing two nitrogen atoms at positions 1 and 4 of the ring.
The numbering system used for these ring compounds begins with one of the carbonyl groups (when present) and continues around the ring to the second carbonyl group (when present) via the two ring nitrogen atoms so the ring nitrogen atoms have the same relative position numbers for all of the compounds embraced by Formula I. Thus, for a ring containing eight atoms and two amido carbonyls, the carbonyl groups are generically numbered to be at the 1- and 6-positions of the ring. The carbonyl groups and their amido nitrogen atoms of those compounds have the same numbers when the ring contains six atoms as in a diketopiperazine compound, even though the carbonyl groups of such a compound are assigned the 2- and 3-positions in a more usual system of nomenclature. Usual organic naming rules are followed for specific componds or libraries such as the 1,4,5-trisubstituted-2,3-diketopiperazines discussed in the examples.
A first of the ring nitrogen atoms of a compound of Formula I, below, is bonded to a C1-C7 alkyl group that contains an amine substituent at the 2-through 7-position from that first amine. For the two carbonyl group-containing compounds, that first ring nitrogen is at ring position 5. For the corresponding compounds lacking the two carbonyl groups, that same nitrogen is at the 4-position of the ring. The second ring nitrogen can also be bonded to a substituent group. Using the above numbering system for the two carbonyl group-containing compounds, the second amine is at the 2-position for the group of compounds having the carbonyl groups and is at the 1-position for those compounds without the carbonyl groups. Compounds also typically contain a ring substituent at the 3-position of a dicarbonyl compound and at the 2-position of a cyclic diamine.
Exemplary structural formulas of some particularly preferred contemplated compounds are provided below based on structural Formulas II or III, hereinafter. Those formulas show the numbering system that is generally used, and in which q is one, and Ra1 and Ra2 and Rb1 and Rb2 are all hydrido and x and y are both one so that the ring positions are more easily seen. 
More specifically, the present invention contemplates individual compounds and synthetic combinatorial libraries of those compounds in which the compounds have a structure corresponding to that shown in Formula I, below, or a pharmaceutically acceptable salt thereof: 
wherein:
q is an integer having a value of 1-7;
W is a saturated or unsaturated chain of 2-4 carbon atoms that are bonded at each terminus of the chain to the depicted nitrogen atoms, wherein (1) zero, one or two of those carbon atoms of the chain is doubly bonded to an oxygen atom, (2)(a) each of the remaining carbon atoms of the chain is independently bonded to one or two substituents selected from the group consisting of a hydrogen atom (hydrido), C1-C10 alkyl, C1-C10 substituted alkyl, C1-C10 phenylalkyl, C7-C16 substituted phenyalkyl, phenyl, substituted phenyl, C3-C7 cycloalkyl, and a C3-C7 substituted cycloalkyl group or (b) two of those remaining carbon atoms of the chain form a saturated or unsaturated mono- or bicyclic ring containing 5- to 8-members in each ring and zero to three heteroatoms in each ring that are independently oxygen, nitrogen or sulfur.
R1 is selected from the group consisting of a hydrido, C1-C10 alkyl, C1-C10 substituted alkyl, C1-C10 phenylalkyl, C7-C16 substituted phenyalkyl, phenyl, substituted phenyl, C3-C7 cycloalkyl, and a C3-C7 substituted cycloalkyl group.
R2 is selected from the group consisting of a C1-C10 alkyl, C2-C10 alkenyl, benzyl, substituted benzyl, naphthyl, or substituted naphthyl group and preferably is a methyl, ethyl, benzyl, allyl, or naphthylmethyl group, and more preferably is a 2-naphthylmethyl group. R2 is most preferably a methyl or benzyl group.
R3 is selected from the group consisting of a hydrogen atom (hydrido), C1-C10 alkyl, C1-C10 substituted alkyl, C1-C16 phenylalkyl, C7-C16 substituted phenylalkyl, phenyl, substituted phenyl, C3-C7 cycloalkyl, and a C3-C7 substituted cycloalkyl group.
R4 is selected from the group consisting of a hydrido, C1-C10 alkyl, C2-C10 alkenyl, C1-C10 substituted alkyl, C3-C7 substituted cycloalkyl, C7-C16 phenylalkyl, C7-C16 phenylalkenyl, C7-C16 phenylalkenyl and a C7-C16 substituted phenyl-alkenyl group.
R5 is selected from the group consisting of a hydrido, C1-C10 acyl, aroyl, C1-C10 alkylaminocarbonyl, C1-C10 alkylthiocarbonyl, arylaminocarbonyl, and an arylthiocarbonyl group.
Another aspect of the invention contemplates individual compounds and synthetic combinatorial libraries of those compounds in which the compounds have a structure corresponding to that shown in Formula II, below, or a pharmaceutically acceptable salt thereof: 
wherein:
each of xe2x95x90Z1 and xe2x95x90Z2 is independently xe2x95x90O, or xe2x95x90Z1 is xe2x80x94Rc1 and xe2x80x94Rc2 and xe2x95x90Z2 is xe2x80x94Rc3 and xe2x80x94Rc4, wherein xe2x80x94Rc1, xe2x80x94Rc2, xe2x80x94Rc3 and xe2x80x94Rc4 are independently selected from the group consisting of a hydrido, C1-C10 alkyl, C1-C10 substituted alkyl, C1-C10 phenylalkyl, C7-C16 substituted phenyalkyl, phenyl, substituted phenyl, C3-C7 cycloalkyl, and a C3-C7 substituted cycloalkyl group.
x and y are independently zero or one, and the sum of x+y is zero, one or two.
q is an integer 1-7.
The dotted line between the carbon atom of Ra1 and Ra2, the carbon atom of Rb1 and Rb2 indicates the presence or absence (i.e., the possibility) of one additional bond between those depicted carbon atoms.
(a) Ra1, Ra2, Rb1 and Rb2 are independently selected from the group consisting of a hydrido, C1-C10 alkyl, C1-C10 substituted alkyl, C1-C10 phenylalkyl, C7-C16 substituted phenyalkyl, phenyl, substituted phenyl, C3-C7 cycloalkyl, and a C3-C7 substituted cycloalkyl group or (b) each of Ra1 and Rb1 is also bonded to the same saturated or unsaturated mono- or bicyclic ring containing 5- to 8-members in each ring and zero to three heteroatoms in each ring that are independently oxygen, nitrogen or sulfur, or (c) one or both of Ra1 and Ra2 and Rb1 and Rb2 together are xe2x95x90O, and wherein both of Ra2 and Rb2 are absent when a double bond is present between the carbon atoms bonded to Ra1 and Rb1.
Substituents R1, R2, R3, R4 and R5 in Formula II are as described above for Formula I.
Another aspect of the invention contemplates individual compounds and synthetic combinatorial libraries of those compounds in which the compounds have a structure corresponding to that shown in Formula III, below, or a pharmaceutically acceptable salt thereof: 
wherein xe2x95x90Z is xe2x95x90O or (xe2x80x94H)2, Ra2 and Rb2 are hydrido or are absent, q, the dotted line, x, y, Ra1, Rb1, R1, R2, R3, R4 and R5 have the meanings provided above.
Compounds and libraries in which q is one, and x and y are both zero are particularly preferred. These compounds correspond in structure to Formulas E1 and E2, below, wherein R1, R2, R3, R4 and R5 are as defined above. 
R5 is preferably hydrido in these compounds and libraries.